Yersinia pestis, in three pandemics, resulted in some 200 million plague deaths and is still endemic throughout the world resulting in sporadic infections. Due to its inability to lead a saprophytic life and its residence in many rodent populations, plague is one of the most feared of zoonotic diseases caused by an obligate animal-human pathogen. The plague bacillus began to be used as a biological weapon at least 800 years ago and is today one of the more likely biological threats. Because of these considerations, we propose to: (i) Construct and evaluate recombinant attenuated Salmonella typhimurium vaccines (RASV) synthesizing Y. pestis K1M antigens in vivo after oral immunization of mice to identify antigens that stimulate protective immunity to challenge with virulent Y. pestis K1M. (ii) Construct and evaluate a recombinant attenuated S. typhi ISP1820 with an RpoS* phenotype to deliver one or more protective Y. pestis KIM antigens. If it is found that different antigen delivery modes are required to induce protective immunity to Y. pestis challenge, we will construct all deemed necessary recombinant vaccines to be administered as a cocktail. (iii) Construct and evaluate a live attenuated Y. pestis vaccine that will induce enhanced immune responses to most, if not all, proteins used by Y. pestis to acquire iron, an important virulence attribute, and exhibit complete biological containment with no surviving bacterial cells after ten generations of growth due to an arabinose-regulated delayed cell lysis system. We will initiate our construction endeavors with Y. pestis KIM6+ that lacks the 70 kb Lcr plasmid and is totally avirulent and add back the Lcr plasmid after introducing attenuating mutations. We will also develop our Master File, prepare and fully characterize candidate vaccine Master Seeds for stability and safety, prepare and submit protocols for IRB approvals, submit information necessary to obtain INDs, and perform any other work needed to arrange that the best candidate vaccines be clinically evaluated in human volunteers.